4,5-Diaryl-imidazoles, in which one of the aryl substituents is a heteroaryl group such as a pyridine or pyrimidine, form an important class of p38 MAPK (mitogen-activated protein kinase) inhibitors, reportedly pursued by a number of pharmaceutical companies as anti-inflammatory drugs (Fullerton, T. et al. Clin. Pharmacol. Ther. 2000, 67, 114). Examples of such pyrimidinyl imidazoles include:

Additional examples of such compounds include inhibitors of protein tyrosine kinases such as: c-Met tyrosine kinase and src kinase (See: U.S. Pat. Appl. Publ. 2005085473; Intl. Pat. Appl. Publ. WO03/087026) for the treatment of, for example, transplant rejection, inflammatory bowel syndrome, rheumatoid arthritis, psoriasis, restenosis, allergic asthma, Alzheimer's disease, Parkinson's disease, stroke, osteoporosis, cancer, and benign hyperplasia; and inhibitors of p38 MAP kinase as anti-cancer (Intl. Pat. Appl. Publ. WO03/087026) and anti-inflammatory agents (Revesz, L. et al. Bioorg. Med. Chem. Lett. 2004, 14(13), 3595-3599); inhibitors of B-raf kinase (Intl. Pat. Appl. Publ. WO01/038324) for the treatment of cancer and neuronal degeneration from ischemic events.
In spite of the heightened interest, preparation of these compounds has relied largely upon two synthetic strategies. Reported methodologies (Liverton, N. J. et al. J. Med. Chem. 1999, 42, 2180-2190; Mcintyre, C. J. et al. Bioorg. Med. Chem. Lett. 2002, 12, 689-692) employed the cyclocondensation of substituted 1,2-dicarbonyl compounds with ammonia and an aldehyde. Although this reaction is quite efficient, preparation of the pyrimidinyl-substituted dicarbonyl derivatives reportedly proceeds through a lengthy sequence starting from 2-mercapto-4-methylpiperidine. Another approach (Adams, J. L. et al. Bioorg. Med. Chem. Left. 2001, 11, 2867-2870, and literature cited therein) involved the cycloaddition of substituted TosMIC with aldimines, originally pioneered by van Leusen (Van Leusen, A. M. et al. J. Org. Chem. 1977, 42, 1153-1159). More recently, Merck scientists have reported a promising one-pot synthesis of imidazoles based on the cyclocondensation of an α-ketoamide with an amine, wherein the requisite α-ketoamide was generated in situ by a Stetter reaction involving an α-amidosulfone (Frantz, D. E. et al. Org. Lett. 2004, 6, 843-846). In these cases also, access to the suitably elaborated pyrimidines required multi-step sequences.
To successfully exploit the particularly efficient condensation of 1,2-diketones bearing an electron-deficient pyrimidine moiety with an aldehyde and ammonia, a more succinct route to the requisite 1,2-diketone derivatives would clearly be advantageous.
To more readily access the desired 1,2-diketone intermediates, we considered the oxidation of disubstituted acetylene compounds, which could be derived from the readily available 2,4-dichloropyrimidine through sequential substitution reactions (Scheme 1). Cyclocondensation of the resulting diketones of Formula (I) would provide the desired pyrimidinyl imidazoles. 1,2-Diketones of Formula (I) are useful in the preparation of pharmaceutically active pyrimidinyl imidazole compounds.
